The formulation of lipophilic, amphipathic, or sparingly water soluble drugs into parenteral and pulmonary dosage forms has proven to be difficult. Successful drug delivery vehicles must be capable of maintaining the drug in its dissolved state over an extended storage period. It is also important that the drug delivery vehicle itself remain stable over the storage period.
Commonly employed delivery vehicles for such drugs include liposome and liposphere compositions. Exemplary of such systems are those drug delivery vehicles set forth in U.S. Pat. Nos. 5,395,619, 5,340,588, and 5,154,930. However, these systems suffer from serious drawbacks. As noted in U.S. Pat. No. 5,395,619, liposome compositions are rapidly cleared from the bloodstream, and various modifications to the liposome systems have been proposed to remedy this problem such as formulating with ganglioside G.sub.M1, coating with polyethylene glycol chains, or attaching polymer compounds to the phospholipid.
Lipid emulsions have also been proposed as alternative delivery vehicles for such drugs. However, the emulsion particle size, generally ranging from about 200 to 1,000 nm, cause these compositions to be readily removed from the blood stream where they tend to accumulate predominately in the liver and spleen. The particle size of the lipid emulsions also precludes the use of filters to sterilize the compositions, thus heat sterilization must be used, which is detrimental to various drugs. From a manufacturing standpoint, lipid emulsions are not preferred due to the requirement of high shear equipment.
Amphipathic drugs containing both hydrophilic and hydrophobic moieties in their structures are frequently poorly soluble in pharmaceutically acceptable oils or aqueous buffers and therefore require administration in potentially irritating compositions containing alcohols or alcohol/surfactant mixtures.
Microemulsions have also been proposed as drug delivery compositions. Microemulsions are generally defined as those systems containing a lipophilic and a hydrophilic component wherein the average particle size of the dispersed phase is below about 150 nm. Microemulsions are further characterized as being clear or translucent solutions. The clarity and particle size characteristics distinguish microemulsions from emulsions. The smaller particle size range of microemulsions enables them to be retained in the blood system for a longer period of time than emulsions. However, microemulsions are generally not dilutable with aqueous fluids, such as certain bodily fluids and buffer solutions, and form emulsions upon contacting such fluids. Various microemulsions are also sensitive to temperature and are not stable outside of room temperature conditions.
A need therefore exists in the art of drug delivery to develop a vehicle that can be used with lipophilic and amphipathic materials and that can be stored at various temperatures for extended periods of time and that can be filter sterilized. The vehicle should also be dilutable with an aqueous fluid such as blood or a buffer solution and still retain these characteristics.